In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

Abstract

Rodenticides are pesticides used worldwide, with little information available regarding health consequences in wildlife and humans. The aim of the present study was to use virtual screening to identify potential targets for flocoumafen, a superwarfarin rodenticide. Blind docking of more than 841 human proteins was carried out employing AutoDock Vina. The strength of the ligand interaction with the proteins was quantified based on the binding affinity score (kcal/mol). Results indicate that flocoumafen could be a promiscuous ligand for diversity of cellular protein targets. The best complexes were obtained for prostaglandin F synthase (−14.2 kcal/mol) and serum albumin (−14.0 kcal/mol) followed by glucocorticoid receptor 2, matrix metalloproteinase-9, nuclear receptor ROR-alpha, and activin receptor type-1, all with values equal or better than −13.5 kcal/mol. Docking method validation based on the root-mean-square deviation showed that flocoumafen had good capability to predict corresponding co-crystallized poses; and molecular dynamics simulations suggested the complex with greater binding affinity was thermodynamically stable. Protein-protein interaction networks built with main protein targets revealed that protein kinase B (AKT1), ribosomal protein S6 kinase B1 (RPS6KB1), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), retinoid X receptor alpha (RXRA), and protein phosphatase 2 catalytic subunit alpha (PPP2CA) were major hub proteins, whereas the gene ontology analysis reported that cellular response to endogenous stimulus, protein binding, and the TOR complex were the biological processes, molecular function, and cell component enrichments, respectively. These results should motivate more ecotoxicity testing for flocoumafen and other superwarfarins, as well as precautionary legislation to minimize exposure to these highly toxic chemicals.

Toxicity of Three Optical Brighteners: Potential Pharmacological Targets and Effects on Caenorhabditis elegans

“…All of the remaining settings were maintained as the default [33]. The validation of this method has been reported in other articles [34,35].…”

l-Proline-catalysed synthesis of chromeno[2,3-b]chromene from 4-hydroxy-2H-chromene-2-thione and an anti-proliferative study

“…Other catalysts like p-TSA or (±) CSA are not effective and produce only trace amounts of product (Table 1, entries 12 and 13). Then, the reaction was carried out in different solvent media, such as water, DMF and DMSO, respectively (Table 1, entries [14][15][16][17]. Reaction in water failed, while in DMF and DMSO, 4a was isolated in 33% and 28% yield, respectively.…”

“…The chemistry of 4-hydroxycoumarin was explored extensively for new compounds, including warfarin, dicoumarol, and flocoumafen, which have significant pharmacological importance and are used as anticoagulants in medicine. [15][16][17][18][19] In contrast, the chemistry of 4-hydroxy-2Hchromene-2-thione (VI), a sulphur-containing analogue of 4-hydroxycoumarin, is far less explored than that of 4-hydroxycoumarin (IV). 20,21 However, 4-hydroxydithiocoumarin (V) and 4-hydroxy-2H-thiochromen-2-one (VII) are two well-studied molecules (Fig.…”

Mapping Protein Targets of Carnosol, a Molecule Identified in Rosmarinus officinalis: In Silico Docking Studies and Network Pharmacology

“…The structure optimized was saved in PDB format. The MGLTools 1.5.0 software was used to add polar hydrogens and convert PDB files to PDBQT format [20,21]…”